Compounds of formula I wherein;
R is C1–C6 alkyl;
R1 and R2 each are independently C1–C4 alkyl, or combine together with the nitrogen atom to which R1 and R2 
n is 2 or 3; or acid salt thereof;are important intermediates in the manufacture of compounds of formula II wherein;
R3 and R4 are independently hydrogen or a hydroxy protecting group; and
R1, R2 and n are as defined above; or a pharmaceutically acceptable salt thereof.
Compounds of formula II, particularly raloxifene hydrochloride, in which R1 and R2 combine to form a piperidinyl moiety, R3 and R4 each are hydrogen, and n is 2, are well known in the pharmaceutical art as having activity for the treatment or prevention of certain disease states including, for example, osteoporosis.
Typically, compounds of formula I are prepared by reacting, for example, β-chloroethylpiperidine hydrochloride and ethyl 4-hydroxybenzoate in methyl ethyl ketone, in the presence of potassium carbonate (see, U.S. Pat. No. 4,418,068). An improved process for preparing compounds of formula I was disclosed in U.S. Pat. No. 5,631,369, the contents of which are incorporated herein by reference. The disclosures of both reference patents teach the use of anhydrous powdered potassium carbonate as the preferred base for enhancing the rate of the reaction, implying that the particle size of anhydrous potassium carbonate is crucial to the alkylation reaction.
Powdered potassium carbonate is relatively more expensive than granular hydrated potassium carbonate, and a controlled atmosphere may be required to maintain the anhydrous nature of powdered potassium carbonate. These factors add to the overall cost of manufacture of compounds of formula I and II.
Furthermore, the use of anhydrous potassium carbonate on a manufacturing scale results in a heterogenous mixture, thus limiting the ability to effectively agitate the mixture. This in turn makes it difficult to perform the reaction at a higher concentration, resulting ultimately in a lower throughput.
A more efficient, more robust and less costly process for preparing compounds of formula I and ultimately compounds of formula II is needed. Such a process would ideally obviate the use of powdered anhydrous potassium carbonate. Such a process would also result in a homogenous reaction mixture which increases reaction concentration and hence throughput. Such a process would be a significant and desirable advancement over the current state of the art. The present invention provides such a process.